Biomedical Research

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Abstract

Background: In limited stage small cell lung cancer, involved field irradiation has been considered as standard. However, there have recent reports suggesting higher than expected nodal recurrence in the supraclavicular region. The study aimed to explore the reasonable radiotherapy range of supraclavicular zone for patients receiving prophylactic or radical radiation.

Keywords

Introduction

Small Cell Lung Cancer (SCLC) remains a major public health
problem and accounts for 10% to 15% of all lung cancers [1].
It has unique clinical features such as rapid growth, early
metastatic spread, and widespread dissemination. At present,
definitive chemoradiation is considered a standard treatment
option for limited disease SCL (LD-SCLC). As a component of
this therapy, radiotherapy is an important integral part of the
management of LS-SCLC, which promotes local control and
also contributes to the survival benefit for patients with limited
disease [2]. Historically, radiotherapy portal included all
mediastinal Lymph Nodes (LNs) and supraclavicular LNs
irrespective of primary tumor extent [3-6]. Due to the
chemotherapy and incidental radiation therapy to subclinical
disease in the uninvolved lymph nodes might have been
sufficient, isolated out-field nodal recurrences are seldom seen.
Hence, it is common to see omission of elective nodal
irradiation applied in clinical practice [7-11].

However, several clinical studies demonstrated that the
involved field radiotherapy (IFRT) by Computed Tomography
(CT) scans or Positron Emission Tomography (PET-CT) in
patients with LS-SCLC resulted in a higher than expected rate
of lymph nodal failures in the supraclavicular region, in
particular for patients with N2/N3 status [9,11-15]. Although
we applied IFRT for those patients, actually, incidental
irradiation has been delivered to the surrounding areas,
especially mediastinal regions [16]. Hence, the lymph nodal
failures in the mediastinal station are extremely rare. However,
supraclavicular region seldom received incidental radiation
therapy, which exposed this region to a relatively high risk of
outfield failure, as was seen in those studies [9,11-15]. In the
current era of precise radiotherapy, the clinical target volume
for radiotherapy is mainly confirmed by CT-images means.
The target area for the mediastinum region and the lower
abdominal region is relatively clear, while supraclavicular
region is not.

In the current study, we performed a retrospective analysis to
investigate the regularity of spontaneous metastasis to lower
cervical lymph nodes in 93 SCLC patients, to explore the
pattern and to find out the high-risk regions of lower cervical
Lymph Node Metastasis (LNM). Finally, we hope to provide
an information concerning the CTV of lower cervical for
SCLC patients.

Methods and Materials

Patients

After obtaining the approval of the institution’s research ethics
board, we performed a single-center retrospective analysis of
453 patients with diagnosed SCLC during 2010 through 2014.
Stage of disease was determined using brain Magnetic
Resonance Imaging (MRI), contrast-enhanced CT of the
cervical, chest and abdomen, bone scintigraphy, and PET-CT
was also used for some patients. The inclusion criteria were as
follows: (1) patients with supraclavicular LNM; (2) there have
lower neck CT scan. The exclusion criteria were mixed
pathology between non-small and small cell cancer, before or
coexisting malignancies.

Definition of lower cervical regions

Currently, there is no uniform standard to partition the
supraclavicular region. On the basis of some studies, we
classified the lower neck into the two sides, the midline of the
body serves as the border between right and left [16-18].
Moreover, each region was classified into 4 groups as upper
para-recurrent laryngeal neural region (UP region), lower pararecurrent
laryngeal neural region (LP region), medial
supraclavicular region (MS region), lateral supraclavicular
region (LS region). Table 1 showed the details of the anatomic
structures for each region. Figure 1 showed the sketch map of
each region at different bedding planes of CT-image.

Zone

Boundary

Upper para-recurrent laryngeal neural region (UP region)

Upper border: lower margin of the cricoid cartilage

Lower border: apex of the right lung and pleural space

Anterior border: anterior border of the carotid artery; posterior border of the trachea

Posterior border: anterior border of the vertebral body

Lateral border: The inside of the internal carotid artery

Lower para-recurrent laryngeal neural region (LP region)

Upper border: apex of the right lung and pleural space

Lower border: upper border of the manubrium

Anterior border: anterior border of the carotid artery; posterior border of the trachea

Posterior border: anterior border of the vertebral body

Lateral border: the inside of the internal carotid artery

medial supraclavicular region (MS region)

Upper border: lower margin of the cricoid cartilage

Lower border: outer edge of junction of internal jugular and subclavian vein, the lower edge of the external jugular vein

Table 1. The bound marks for CT image-based zoning of supraclavicular lymph nodes of patient with small cell lung cancer.

Figure 1: Schematic diagrams of zoning at different bedding planes of
CT-imaging in lymphatic drainage area. Regions encircled with red
line are UP region, with blue line are LP region, with yellow line are
MS region, and with orange line are LS region.

Diagnostic criteria for LNM

(1) A single LN with a short axis>10 mm, or a single LN with
a short axis<10 mm combined with hoarseness or vocal cord
paralysis, or there are more than three LNs in the same
mediastinal region on enhanced CT-images.

(2) The presence of necrosis, markedly inhomogeneous
enhancement on enhanced CT scans; positive LNs appeared at
uncommon regions; fluorodeoxyglucose-avid (if used); and the
response to anti-tumor therapy was obvious [19-21]. All
images were reviewed and interpreted by 2 experienced
radiological experts.

Lymph node depicting

The positions of the metastatic lower cervical LNs for all
enrolled patients were re-read respectively and then recorded
the positions of positive LNs based on previous literature
[21,22].

Results

Patient characteristics

After the inclusion and exclusion criteria, 93 patients were
included in this study. Clinical Features of Patients with SCLC
and the characteristics of tumor are summarized in Table 2.
The median age of those patients included in this study was 57
years (range, 48-74 y). Of these 93 patients, 67 patients were
male and 26 female. Of the 93 patients whose records were
examined, a total of 138 metastatic LNs were found in the
lower cervical region, and the number of positive LNs per
patient ranged from 1-3. Among all 138 nodes, 47.1% located
on the left and 52.9% located on the right.

According to our study, most lymph node metastasis sites are
located in the MS region and LP region (83.3%, 115 of 138
nodes). These two regions are high risk areas for lymph node
metastasis. Therefore, if consider prophylactic radiation to the
lower neck, only the MS region and LP region need to be
included in Clinical Target Volume (CTV).

Omission of uninvolved nodal stations in radiation therapy is a
straightforward strategy to reduce the radiation related toxicity,
as has been recently reported [7,9,12,13,23]. However, the use
of involved-field radiotherapy (IFRT) or Elective Node
Irradiation (ENI) in LS-SCLC remains controversial [24].
Although IFRT is becoming common in contemporary clinical
practice, high-level evidence to support the practice of
omission of ENI is still rare. Recently, several clinical studies
reported that a high incidence of local nodal failure, were noted
in supraclavicular fossa in patients of LS-SCLC. Tada et al.
[25] examined the pattern of failures in patients with SCLC
treated with IFRT. The results showed that patients with N2 or
N3 LS-SCLC appeared to have more regional relapses in the
upper mediastinum and supraclavicular fossa. Similarly, De et
al. [12] demonstrated that the IFRT on the basis of CT scans in
patients with SCLC resulted in a higher than expected rate of
isolated nodal failures in the supraclavicular fossa. Recently, a
prospective study conducted by Hu et al. [11] reported patterns
of recurrence after IFRT in LS-SCLC. In their study, isolated
nodal recurrences, which all in the ipsilateral supraclavicular
fossa, were reported with mediastinal N3 disease in 100%
patients. Therefore, based on their preliminary results, in one
of his studies, N3 disease patients will receive prophylactic
irradiation to the ipsilateral lower neck. Accurately delineating
the scope of irradiation range is the prerequisite for treatment.
However, accurate determination of the appropriate range of
radiation is challenging for clinical practice.

At presents, there is still no relevant recommendation for
radiotherapy in supraclavicular lymph node zone of small cell
lung cancer. Target volumes are often defined primarily on the
basis of the distribution of normal lymphatics or by vascular
and bony landmarks. A large lateral extent of the irradiation
field theoretically brings a greater regional control. However,
the more generous coverage discussed herein must be balanced
by an awareness of potential toxicities associated with
treatment. Extensive research indicated that a large lateral
extent of the lower neck irradiation field could bring more
toxicity by irradiating extra volumes, especially lymphedema,
lung damage, and brachial plexopathy. A study performed by
Graham et al. investigated the effect of Supraclavicular Fossa
(SCF) radiotherapy volumes on the development of
lymphoedema. The results showed that irradiation field lateral
to the coracoid process was a significant risk factor for
lymphedema (P=0.002) [26]. In the MA.20 trial, the irradiation
field included the head of clavicle medially and the coracoid
process laterally and the levels I and II axilla in some patients.
The results showed that those patients had higher rates of
lymphedema (8.4% vs. 4.5%; P=0.001) and acute pneumonitis
(1.2% vs. 0.2%; P=0.01) [27]. Those dates indicated that
irradiating extra volumes would be associated with more
toxicity. Hence, it is important to accurately define the
supraclavicular nodal region at risk, which could better cover
target areas and spare normal tissues. The central aim of this
study was to characterize the distribution of these nodes
according to CT scan in patients with supraclavicular regional lymph node involvement and to use this evidence to suggest
contours of the reasonable CTV margin in the supraclavicular
zone. Recently, Luo et al. [28] explored the distribution pattern
of lower cervical metastatic lymph node in esophageal cancer
and found that supraclavicular zone metastasis frequently
occurred in the cervical paraesophageal lymph nodes and lower
cervical fossa. Inconsistent with the study of EC. As shown in
Table 3, metastasis frequently occurred in MS region and the
LP region for SCLC patients. While the incidence in others
region is low, it may be reasonable to exclude these lymph
nodes from the CTVn. Based on this study, the MS region and
LP region are considered to be the high risk regions for LNM,
which were the regions for prophylactic irradiation.

There are some limitations in this study. Firstly, it was a
retrospective study, our data originated from a single institution
and the sample size of the present study was not enough.
Furthermore, the diagnosis of positive LNs in the present study
was on the basis of image data, rather than pathological
evidence. Thus, we cannot make sure that all of the enlarged
lymph nodes contain metastatic lesions. Fortunately, Most of
the patients with lower cervical metastases in the study were
underwent the PET/CT image, and PET/CT is generally
reported to have a high rate of sensitivity and specificity in this
setting [13,29,30]. Thus, the outcome of our study is credible.

Conclusion

In a word, the study we conducted was aimed to provide a
reference for the supraclavicular region target delineation of
SCLC. If prophylactic irradiation therapy is considered, the
target zones for prophylactic irradiation should include MS
region and LP region as recommended.